The present invention relates to a viscoelastic material for use in medical procedures, particularly for placement into the eye during ophthalmic surgical procedures to maintain the shape of the eye and to protect delicate tissue lining the inner walls of the eye.
Cataracts in human eyes, a clouding of the lens which severely effects vision and can render an individual blind, have been removed by surgical procedures for centuries. One of the earliest techniques, known as couching, utilized a long thorn to pry lose the clouded lens. However, safe and effective cataract removal followed by the implantation of an artificial lens has been practiced only since the early 1970's. Prior to then the patient was usually fitted with thick glasses in an attempt to provide at least some acceptable level of vision after removal of the clouded lens. Cataract removal and artificial lens implantation is now performed in the United States on over one million patients per year.
One of the hazards of the cataract removal and lens implantation procedure is the fact that the inside cell layer of the cornea (corneal endothelium) as well as other internal tissues is very sensitive to abrasion or inadvertent contact. In particular, damage to, or removal of, the cells on the cornea may compromise corneal physiology and lead to corneal edema, opacification and eventually complete loss of the cornea.
As a result, a great deal of effort has been devoted to protecting the corneal endothelium, during cataract surgery. In particular, various different materials have been injected into the anterior portion of the eye including balanced salt solution, an air bolus (both of limited utility as they are easily dispersed from the eye) and viscoelastic materials. Viscoelastic materials prepared from various naturally occurring substances or synthesized in the laboratory include sodium hyaluronate, chondroitin sulfate and combinations thereof, cellulosic materials, and polymers based on acrylamide. While viscoelastic materials remain in the eye and offer better protection to the ocular tissue, each of the prior used viscoelastics have disadvantages which included allergic reactions, neurotoxic impurities, inadequate viscosity or viscoelasticity, unacceptable levels of particulate materials, gels or bulky polymer chains which enter and plug the trabecular mesh work causing excessive intraocular pressure in the eye, variation in properties from batch to batch due to variability of naturally occurring raw materials, and excessive cost. These materials, because they result in increased ocular pressure also generally require that they be irrigated from the eye. Further, hyaluronic acid based materials also require refrigerated storage and may have a limited shelf life.
The use of prior art hydroxypropylmethylcellulose solutions in animal toxicity studies has shown that these materials are generally non-toxic both locally and systemically when ingested or injected into various animal systems. Also, various prior art HPMC formulations in intraocular use have been shown to be non-toxic to endothelial cells and to result in only minimal and transient intraocular pressure rise and to clear the eye rapidly.
Dow Chemical Company has studied the toxicology and metabolic fate of HPMC polymers extensively to support the use of their Methocel trademark HPMC. These studies have shown that the polymer is non-pyrogenic, non-immunogenic, non-cytotoxic, non-toxic in extended animal metabolic studies, is not metabolized and is rapidly eliminated after ingestion. The majority of these reports deal with the tolerance of animal systems to HPMC via feeding studies. However, a review of the data on toxicology reveals that intradermal and vascular injections of HPMC polymers in mice and rats do not provide any evidence of toxicity, teratogenicity, or other negative metabolic effects. It is concluded from these reports that HPMC polymers do not interfere with normal animal metabolism, are not themselves metabolized, and are filtered from the bloodstream into the kidneys and excreted without negative effects to the animal systems studied. In confirmation of these studies, the Dow Chemical Company Methocel brand of HPMC has been issued Drug Master File No. 76 by the Food and Drug Administration.
Robert et al have provided evidence of the lack of systemic toxicity of intraocular injections of 2% HPMC solutions into rabbit eyes. (Robert, Y., Gloor, B., Wachsmuth, E. D., Herbst, M., "Die Uberprufung der Vertraglichkeit von Intraokular injizerter Hydroxypropylmethylcellulose im Tierversuch," Klin Montasbl Augenheilkd, 192:337-339, 1988.) These researchers injected aliquots of a 2% HPMC solution into rabbit anterior chambers, and into rabbit posterior chamber vitreous, and followed the course of intraocular and systemic changes for 12 days. They found no intraocular changes, and also no systemic changes. These results clearly demonstrate that the HPMC polymer is non-toxic to the animal eyes and is systemically non-toxic in rabbits.
The available evidence in the literature demonstrates that HPMC is not metabolized by mammalian systems, is non-toxic on oral, intradermal, intraocular and vascular introduction, and is safely cleared from the systems via excretion in the urine. Thus it may be inferred from these reports that HPMC solutions are safe for human intraocular and systemic use.
HPMC solutions have been used as intraocular viscoelastic surgical fluids for several years in Europe, the USA, and elsewhere. The literature reports on the clinical use of HPMC solutions reflect a general consensus that these polymers are safe and effective for use as ophthalmic viscoelastic surgical fluids, easy to use and do not result in inflammatory reactions or excessive intraocular pressure postoperatively, but are only marginally equivalent to hyaluronic acid products in ability to maintain the chamber and protect the endothelium during cataract surgery.
However, the use of HPMC solutions for intraocular surgery has been criticized by Rosen. (Rosen, E. S., Gregory, R. P. F., Barnett, F., "Is 2% hydroxypropyl methylcellulose a safe solution for intraoperative clinical applications?" J. Cataract and Refractive Surgery, 12:679 (1986); Rosen, E. S., "The use of hydroxypropyl methylcellulose in extracapsular cataract extraction with intraocular lens implantation," Am J. Ophthalmology, 103:727 (1987)). Rosen bases his criticism on the microscopic examination of HPMC preparations produced by hospital pharmacies in Europe. Rosen reports that significant amounts of debris and particulates are found in these and other commercial preparations, which could lead to problems during surgical use. Further, Rosen states that current attempts to filter HPMC have been ineffective and "it seems to be impossible to prepare HPMC solutions for clinical use without a degree of particulate vegetable matter content." However, Momose et al report that counts of the particulate levels by automated laser particle counters reveal that 2% methylcellulose preparations prepared in his institute actually had fewer large particles than commercially available hyaluronic acid preparations. (Momose, A., Baba, T., Kasahara, A., "Particles in Viscosurgical Materials," Journal of the Eye, 5:314 (1988)).
Fernandez-Vigo et al. reported in 1989 that the half life of clearance of various concentrations and viscosities of HPMC solutions from rabbit eyes was in the range of 3 to 4 1/2 hr. (Fernandez-Vigo, J. F., Refojo, M. F., Jumblatt, M., "Elimination of hydroxypropylmethylcellulose from the anterior chamber of the rabbit," J. Cataract Refractive Surgery, 15:191 (1989)). Their experiments involved introduction of large doses of relatively low molecular weight HPMC solutions (86,000 or 120,000 Daltons) into rabbit eyes, and assays of the HPMC remaining after various periods of time. They found that after 24 hr., there were no detectable amounts of HPMC remaining in the samples of aqueous removed from the rabbit eyes. They concluded that HPMC clearance was complete within 24 hrs. The authors also concluded that the removal of the HPMC from the eye was by the normal trabecular meshwork outflow system, with no metabolic degradation within the eye. Their report further found no damage to endothelial cells, only a transient increase in intraocular pressure after the injection of the HPMC solutions within the eye, and no long term inflammatory reactions.
Jacobi et al reported that their studies of the intraocular (anterior chamber and intravitreal) injections of HPMC solutions into the rabbit resulted in no inflammatory reactions, only transient rise in intraocular pressure, and rapid clearance from the eye. (Jacobi, K. W., Schott, K., Gloor, B., "Kongress der Deutschen Gesellschaft fur Intraokularlinsen Implantation," Berlin, Springer-Verlag, 1987 pp 86-89.) They concluded that the HPMC was cleared from the eye by the normal outflow mechanism, and was diluted into the bloodstream.
These published evaluations of the rapid clearance of HPMC polymer from the eye demonstrate that this polymer does not interfere biochemically with the normal aqueous clearance through the trabecular meshwork, and only raises intraocular pressure transiently due solely to its high molecular weight and viscosity.
However, these solutions still contain unnecessarily high levels of particulate contamination. Additionally, the prior art solutions are composed of low molecular weight HPMC materials and thus, to obtain the desired viscosity higher concentrations of HPMC must be used, thus increasing the possibility of introducing a higher percentage of contaminants. Further, because the polymers have a lower molecular weight, the solutions may not have a suitable viscoelasticity. The prior art ophthalmic HPMC solutions, because they were prepared from lower molecular weight materials had viscosities of about 4,000 to 5,000 cps at 25.degree. C. As a result, these materials also were not very viscoelastic. Additionally, they had high levels of particulate material. As a result, they could not be filtered through a 0.5 .mu.m filter as the filter pores became immediately plugged as the material passed through the filter. A further problem with prior art HPMC solutions was the tendency to dehydrate when autoclaved at temperatures above 100.degree. C. resulting in large amorphous aggregates. Most of these aggregates would rehydrate upon cooling but a significant portion remained permanently insoluble. Prior art autoclaving and cooling procedures following autoclaving also resulted in the release and suspension of gas bubbles in the resultant gels and the compositions did not have a uniform viscosity distribution, the more viscous, higher molecular weight materials tending to settle to the lowest point in the container.
Thus there is a need for a low cost, stable, high viscosity material for use in ocular surgical procedures which is nontoxic and allergy free and is free of particulate material or gels which can cause an increase in intraocular pressure. In particular, there is a need for a high viscosity, low HPMC concentration solution prepared from high molecular weight material which is substantially free of harmful particulate material.